by Barbara Unger, GMP Quality Expert, and GMP Regulatory Intelligence Editor-in-Chief
China published their annual report of drug inspections for 2016 on June 2, 2017. The 31-page document reports on a variety of inspection types including but not limited to: pre-approval inspections, GMP certification inspections, and GMP follow-up inspections. The report is accompanied by tables and figures. For the most part, it is easily understood, but where discrepancies seem to appear between the various values and terminology, I’ve highlighted the uncertainty. Some types of inspections are absent here, but the report provides specific details on the inspections and the deficiencies identified.
First, we’ll look at the overview of the inspections conducted by Chinese FDA authorities in 2016. In addition, this report summarizes 81 inspections conducted by international health authorities alongside the FDA. Data in the tables are taken directly from the report.
|Type of Inspection||Number of Inspected “Enterprises / Varieties”|
|GMP Certification Inspection||16|
|GMP Follow-up Inspection||204|
|GSP Unannounced Inspection||50|
|International Inspections (CFDA as observers)||81|
The number of pre-approval inspections decreased gradually from the 160 seen in 2012 to the mere 114 that took place in 2015. In 2016, 34 inspections were conducted – a significant reduction from the 114 inspections performed in 2015. These pre-approval inspections addressed APIs (35%), pharmaceutical products (29%), biological products (23%), traditional Chinese medicines (10%), and blood products (3%).
Among the deficiencies were failures in data integrity, insufficient process validation, and no investigations of deviations. Failures in data integrity were common and reflected the inability to trace testing data, batch production records that were inconsistent with the filed dossier, or untruthful or incomplete data. Process validation was insufficient, producing batches with serious deviations or yield that was significantly different from the validation batch(es). Finally, investigations were not conducted into ‘significant abnormality in dynamic production’. Routine production batches showed ‘significant difference in the rate of finished products’. I interpret this to mean that routine production did not align with the state of control demonstrated by the validation batches. Further, due to a lack of investigation into the issue, the root cause failed to be identified.
Sixteen Pharmaceutical GMP Certification Inspections were conducted for the following product types: LVPs (3), SVPs (3). Freeze dried powder injection (3), Powder Injection (1), Radiopharmaceutical (1), Vaccine (2), and Biologics (3). For these 16 inspections, a total of 220 deficiencies were identified – 23 of which can be classified as major. Deficiencies were identified in QC and QA, Documentation Management, Personnel, Equipment, and Verification / Qualification.
Two in vitro diagnostics reagent manufacturers both failed inspections. Shortcomings in this area involved failures in the Quality Management System, scarcity of trained experienced personnel, poor documentation, incomplete data, and changes applied apart from appropriate change controls. Process validation was not conducted for all products, cleaning validation was lacking, and part of the validation records were incomplete.
A total of 204 GMP Follow-up Inspections were conducted in 2016, deviating from the planned 262 inspections. Inspections were comprehensive with twenty-one (21) sterile drug manufacturers, sixty-seven (67) manufacturers of high-risk ‘varieties’, twenty-five (25) blood product manufacturers, and thirty-six (36) vaccine manufacturers. Outcomes for the inspections in these categories include:
- 21 of 21 sterile drug manufacturers passed the inspection
- 64 of 67 manufacturers of high risk varieties passed the inspection
- 25 of 25 blood product manufacturers passed the inspection
- 36 of 36 vaccine manufacturers passed the inspection
Warning letters were issued to selected firms in each of the categories, but the inspection outcomes in these cases seemed to be ‘pass’ so it appears that ‘warning letters’ do not necessarily indicate a failed inspection.
Taken as a whole, the deficiencies identified in this group of inspections encompass similar areas: data integrity, data management, computer systems, documentation, process control, and validation. The report itself addresses each of the category types within this group of inspections with figures identifying each of the areas of deficiency.
Thirty-nine unannounced inspections were completed, and six additional inspections are reported in progress. Results for these inspections are in the following table reproduced from the annual report.
|Product Category||Number of Inspections||Failures||Revoked GMP Certificates||Product Recalls|
|Traditional Chinese Medicines||20||14||9||2|
Clearly, the traditional medicines category saw the most enforcement actions in terms of inspection failures, revoked GMP certificates, and product recalls. Biochemical drugs were nearly as problematic with more than 50% failing their inspections, and almost half had their GMP certificates revoked along with product recalls. The category of “Chemicals” fared best with only one of nine inspection failures, no revoked GMP certificates, and no product recalls.
Only 7 overseas inspections were carried out in 2016, although forty-nine were originally planned. Three of the seven inspections failed. Withdrawal of import registration certificate or application withdrawal and difficulties in production scheduling for identified facilities resulted in delays of inspection. The forty-nine planned inspections were identified for 19 countries; thirty-three were scheduled for European countries. Deferred 2016 inspections were moved to 2017.
In the seven inspections conducted, 117 deficiencies were identified with 3 critical and 18 major deficiencies. The critical deficiencies were associated with control of the manufacturing process and data integrity. Deficiencies were also identified in QC and QA, Materials System, and Change Management. Figure 5-6 in the report provides detail on the areas involved in deficiencies.
The report also contains a large section on Good Supply Practice for Pharmaceuticals with several tables and figures that provide detail on the specific issues. Among the main deficiencies identified were: having “false and cheating behaviors” and failing to operate in accordance with the law; failure to ensure drugs are stored under correct environmental conditions and failure to monitor temperature and humidity in the warehouse; inconsistent documentation of goods and payment.
The final group we’ll discuss is the 81 inspections conducted by twelve foreign health authorities such as the WHO, FDA, EDQM, ANVISA. Nine of the manufacturers were identified to have critical deficiencies and failed the inspections. The nine inspections were conducted by investigators from the WHO, FDA, and EDQM. Here too, data integrity failures are the most common reason for critical deficiencies including “…conducting repeated tests until qualified, conducting tests after changing system time, deleting data, deleting the audit and tracking records, selectively using data, modifying the name of the electronic data, test sample injection, failing to record timely, untruthful records, loss of data and records, insufficient file record control, etc.” Most (69%) of the inspections were for APIs followed by solid oral dosage form inspections (13%) and injectables (11%).
The foreign inspections identified 1108 deficiencies in QA and QC, Documentation Management, Equipment, Materials and Products, Verification and Qualifications (assuming this also accounts for validation), and Premises and Facilities. Deficiencies for the top three categories included:
- Quality Control and Quality Assurance: ‘…management of computerized analysis instruments in the laboratory, deviation handling and CAPA, product quality review, change control, OOS/OOT result processing, the laboratory’s failing to meet the provisions for control procedure, microbial inspection management, quality risk management and stability test.’
- Documentation Management: ‘…completeness and traceability of records, life cycle management of documents, document completeness and record operation.’
- Equipment: ‘…using and cleaning, calibration, maintenance, and repair of equipment and water preparation system.’
And, finally, foreign inspectorates differed in the number of deficiencies they identified. The EDQM and WHO identified an average of twenty at each inspection and the FDA averaged 7.
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